An interesting poster at IAS 2013 looked at the association between HLA incompatability of sexual partners as a mechanism for protection against sexual transmission. 1

Wim Jennes from the Institute of Tropical Medicine, Antwerp presented results from a study of 108 Senegalese couples enrolled in a cohort in Dakar. This included 35 sero-different couples, 35 where both partners were HIV positive and 38 where both partners are HIV negative.

The hypothesis for potential protection was based on the role that killer immunoglobulin-like receptors (KIR) which regulate natural killer (NK) innate immune responses in susceptibility to HIV infection and that KIR respond to HLA expression on target cells. The group has previously published on how KIR/HLA patterns could explain protection from HIV in a group of multiply-exposed HIV negative sex workers. 2

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KIR contain two or three external Ig-like domains (2D, 3D) with either long (2DL, 3DL) or short (2DS, 3DS) tails, corresponding to their function as inhibitory or activating receptors, respectively and can have strong or weak binding affinities to specific HLA.

In the in vitro studies with HIV negative cells, significantly higher levels of alloreactive NK cell-mediated CD4 killing were seen for missing self KIR/HLA combinations.

Comment

The complexity of factors that compound to allow or block sexual transmission are numerous and complex, and range from biomedical determinants to behavioural risks. In terms of individual per-exposure risks reference ranges (approximately 1 in 200-500 in someone not on treatment) suggest that HIV is a difficult virus to transmit.

Conversely, only one exposure is needed for transmission to occur. Anecdotally, some people are unlucky in this corresponding to a single unprotected risk while others remain protected after numerous risks over many years with an HIV positive partner, even when condoms are not used.

Although free virus is usually referred to as the cause of infection, HIV-1 transmission may occur at least in part via HIV infected cells from the sexual partner. These cells can penetrate deeply in the recipient's mucosal tissues and continue to produce infectious virus. The relative contribution of free virus and infected cells in causing transmissions is not known. The current hypothesis from this group is that the allogeneic KIR/HLA mismatches protect against these incoming infected cells.

Once infection is established, even if this is by free virus from the sexual partner, they suggest that an early mucosal infection in the recipient could then still be cleared by autologous activating KIR/HLA genotypes in the recipient partner. They also speculate that that alloreactive KIR/HLA combinations target free virus from the sexual partner, because free virus is known to carry the HLA molecules from the host cells in abundance on the viral membrane. The mechanism for this requires further study.

A previous analysis of these couples, published in PLoS One, reported a high phylogenetic linkage between the positive couples (74% linked, 13% indeterminate, 13% unlinked) that corresponded to interview data on behavioural risk. 3

Also, that although condom use is now high in the serodifferent couples, and that many of the HIV positive partners have suppressed viral load due the ART, the negative partners still represent selected survival because they went through a period of high infection risk (when HIV status was not known, no condom use and no ART). These issues are expanded on in the published findings from this study in the journal Blood. 4

This research provides insight into further understanding the genetic factors affecting transmission and is important for highlighting how these may be specifically partner dependent.

References

Unless stated otherwise, references are to the Programme and Abstracts for the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 30 June  3 July 2013, Kuala Lumpur.

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